Kupffer Cells Promote Hepatic Steatosis Via Interleukin-1β–Dependent Suppression of Peroxisome Proliferator-Activated Receptor α Activity

Stienstra, Rinke; Saudale, Fredy Z.; Duval, Caroline; Keshtkar, Shohreh; Groener, J.E.M.; Rooijen, Nico van; Staels, Bart; Kersten, Sander; Müller, Michael

doi:10.1002/hep.23337

Cited by 411 publications

(331 citation statements)

References 53 publications

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“…strong inflammatory response [35,36] . Interestingly, the amount of MUFA was increased relative to SFA and PUFA in p62 transgenic animals, indicating that there are alterations in the fatty acid metabolism in both NASH and NASH-related HCC [3,6] .…”

Section: Ementioning

confidence: 99%

Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis

Simon

Kessler

Gemperlein

et al. 2014

WJG

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AIM:To characterize how insulin-like growth factor 2 (IGF2 ) mRNA binding protein p62/IMP2-2 promotes steatohepatitis in the absence of dietary cholesterol. METHODS:Non-alcoholic steatohepatitis (NASH) was induced in wild-type mice and in mice overexpressing p62 specifically in the liver by feeding the mice a methionine and choline deficient (MCD) diet for either two or four weeks. As a control, animals were fed a methionine and choline supplemented diet. Serum triglycerides, cholesterol, glucose, aspartate aminotransferase and alanine transaminase were determined by standard analytical techniques. Hepatic gene expression was determined by real-time reverse transcription-polymerase chain reaction. Generation of reactive oxygen species in liver tissue was quantified as thiobarbituric acid reactive substances using a photometric assay and malondialdehyde as a standard. Tissue fatty acid profiles and cholesterol levels were analyzed by gas chromatographymass spectrometry after hydrolysis. Hepatocellular iron accumulation was determined by Prussian blue staining in paraffin-embedded formalin-fixed tissue. Filipin staining on frozen liver tissue was used to quantify hepatic free cholesterol levels. Additionally, nuclear localization of the nuclear factor kappa B (NF-κB) subunit p65 was examined in frozen tissues. RESULTS:Liver-specific overexpression of the insulin-like growth factor 2 mRNA binding protein 2-2 (IGF2BP2-2/IMP2-2/p62) induces steatosis with regular chow and amplifies NASH-induced fibrosis in the MCD mouse model. Activation of NF-κB and expression of NF-κB target genes suggested an increased inflammatory response in p62 transgenic animals. Analysis of hepatic lipid composition revealed an elevation of monounsaturated fatty acids as well as increased hepatic cholesterol. Moreover, serum cholesterol was significantly elevated in p62 transgenic mice. Dietary cholesterol represents a critical factor for the development of NASH from hepatic steatosis. Filipin staining revealed increased free cholesterol in p62 transgenic livers, which were not diet-derived. The mRNA levels of the rate-limiting enzyme for cholesterol synthesis 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase or HMGCR) were not significantly upregulated, potentially due to increased cholesterol biosynthesis via elevated sterol regulatory element binding transcription factor 2 (SREBF2 ) gene expression and increased iron deposition in transgenic animals. CONCLUSION:This study provides evidence that p62/IGF2BP2-2 drives the progression of NASH through elevation of hepatic iron deposition and increased production of hepatic free cholesterol.

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Section: Ementioning

confidence: 99%

Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis

Simon

Kessler

Gemperlein

et al. 2014

WJG

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“…The authors also highlighted that the reduction of the NKT cell population is due to the activation of Kupffer cells via an endotoxin-mediated mechanism. Furthermore, Stienstra et al (26) demonstrated a relevant role of the Kupffer cells in hepatic triglyceride storage, promoting hepatic steatosis by means of IL-1β-mediated suppression of peroxisome proliferator-activated receptor α (PPAR-α) activity.…”

Section: Introductionmentioning

confidence: 99%

Markers of activated inflammatory cells correlate with severity of liver damage in children with nonalcoholic fatty liver disease

et al. 2012

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Abstract. Concomitantly to the obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become the leading cause of liver disease in children. NAFLD encompasses a spectrum of histological damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), with possible progression to cirrhosis. There is growing evidence that the immune system plays a pivotal role in the initiation and progression to NASH but the cellular nature of the hepatic inflammation is still unknown. The present study includes 34 children with biopsy-proven NAFLD. Liver damage was evaluated by the NAFLD activity score (NAS), and the inflammatory infiltrate was characterized by immunohistochemistry for CD45, CD3 and CD163 which are markers of leukocytes, T cells and activated Kupffer cells/macrophages, respectively. Our results have shown that CD45 + (P<0.0001) and CD163 + (P<0.0001) cells were markedly increased in children with severe histological activity (NAS≥5) compared to children with lower activity (NAS<5), whereas CD3 + cells were significantly lower (P<0.01) in children with severe histological activity. There was a significant association between the numbers of CD45 + , CD3 + and CD163 + cells, regarding both the portal tract and liver lobule, and the severity of steatosis, ballooning and fibrosis (P<0.01). These data suggest that the severity and composition of the inflammatory infiltrate correlate with steatosis and the severity of disease in children with NAFLD. Moreover, a decrease in CD3 + cells may be involved in the pathogenesis of liver damage. Future studies should evaluate whether it can predict the progression of liver disease independently of established histological scores.

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“…31 In consistent with our results, Stienstra et al showed that IL-1β promotes liver steatosis and fibrosis. 32 Among the most investigated adipokines, adiponectin, visfatin and leptin seem to play a prominent role in the pathogenesis and progression of NASH. 5 Adiponectin is an adipocyte derived cytokine and is considered as an anti-inflammatory adipokine and TNF-α antagonist.…”

Section: Discussionmentioning

confidence: 99%

Beneficial effects of diacerein on adipokines and pro-inflammatory cytokines involved in diet-induced nonalcoholic steatohepatitis in rats

Allah

2017

Int J Basic Clin Pharmacol

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Background: Non-alcoholic steatohepatitis (NASH) is considered as a progressive liver disease, so effective therapies are needed to ameliorate hepatic steatosis, inflammation and fibrosis, and to prevent the progression to cirrhosis and hepatocellular carcinoma. Diacerein is an anti-inflammatory drug that inhibits the synthesis and activity of pro-inflammatory cytokines. The present study was designed to investigate the effect of diacerein on pro-inflammatory cytokines as well as adipokines involved in diet-induced NASH rat model.Methods: Thirty-two adult male rats were divided into four groups: control, diacerein-treated, NASH-untreated and NASH+diacerein-treated groups. NASH was induced by feeding rats with high-fat and high-cholesterol diet for 12 weeks. Body weight, liver weight, fasting blood glucose and insulin levels for estimation of insulin resistance, blood lipids, alanine transaminase, and aspartate aminotransferase were evaluated. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), adiponectin, visfatin and leptin were also detected. Histopathological examination of liver sections was performed.Results: Diacerein significantly reduced liver weight, fasting blood glucose, insulin level, transaminases and ameliorates insulin resistance with favourable effects on blood lipids. These results were accompanied with a significant reduction in serum levels of TNF-α, IL-1β, IL-6, and visfatin, while, adiponectin was significantly increased and leptin was insignificantly affected. Liver sections revealed that diacerein reduced steatosis and lobular inflammatory grades.Conclusions: These data suggest that diacerein administration may have a potential usefulness in the prevention of NASH as a possible result of inhibition of pro-inflammatory cytokines and the beneficial effects on adipokines especially adiponectin and visfatin.

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Kupffer Cells Promote Hepatic Steatosis Via Interleukin-1β–Dependent Suppression of Peroxisome Proliferator-Activated Receptor α Activity

Cited by 411 publications

References 53 publications

Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis

Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis

Markers of activated inflammatory cells correlate with severity of liver damage in children with nonalcoholic fatty liver disease

Beneficial effects of diacerein on adipokines and pro-inflammatory cytokines involved in diet-induced nonalcoholic steatohepatitis in rats

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